BACKGROUND Immune checkpoint inhibitor(ICI)-induced rheumatic immune-related adverse events(ir AEs)have been infrequently reported,and the treatment of severe or refractory arthritis as ir AEs has not been established...BACKGROUND Immune checkpoint inhibitor(ICI)-induced rheumatic immune-related adverse events(ir AEs)have been infrequently reported,and the treatment of severe or refractory arthritis as ir AEs has not been established yet.CASE SUMMARY The patient was a 67-year-old man with a history of well-controlled foot psoriasis who presented with polyarthralgia.He had received pembrolizumab for metastatic gastric adenocarcinoma 2 mo previously.Physical examination revealed erythematous swelling in the distal interphalangeal joints,left shoulder,and both knees.He had plaque psoriasis with psoriatic nail dystrophy and dactylitis in the distal joints of the fingers and toes.Inflammatory markers including C-reactive protein and erythrocyte sedimentation rate were elevated but rheumatoid factor and anticyclic citrullinated peptide antibody were negative.The patient was diagnosed with psoriatic arthritis(PsA)and started on methylprednisolone 1 mg/kg/day after pembrolizumab discontinuation.However,despite 1 wk of methylprednisolone treatment,PsA worsened;hence,leflunomide and methotrexate were started.After 4 wk of steroid treatment,PsA worsened and improved repeatedly with steroid tapering.Therefore,the therapy was intensified to include etanercept,a tumor necrosis factor inhibitor,which ultimately resulted in adequate PsA control.CONCLUSION This is the first report of ICI-induced PsA in a gastric cancer patient.Some rheumatic ir AEs with refractory severe arthritis may require disease-modifying anti-rheumatic drugs and long-term management.展开更多
Compensated liver cirrhosis(CLC)is defined as cirrhosis with one or more decompensating events,such as ascites,variceal haemorrhage,or hepatic encephalopathy.Patients with CLC are largely asymptomatic with preserved h...Compensated liver cirrhosis(CLC)is defined as cirrhosis with one or more decompensating events,such as ascites,variceal haemorrhage,or hepatic encephalopathy.Patients with CLC are largely asymptomatic with preserved hepatic function.The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors.The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis,as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years.Furthermore,early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition.With the advent of effective non-invasive tools for detecting hepatic fibrosis,more and more patients with CLC are currently being recognised.This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or,at the very least,prevent its progression.There are numerous emerging approaches for preventing or delaying decompensation in CLC patients.A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression,and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension.Additionally,address-ing various cofactors(such as obesity,diabetes,dyslipidaemia,and alcoholism)and precipitating factors(such as infection,viral hepatitis,and hepatotoxic drugs)that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC.However,high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these diseasemodifying techniques for CLC patients.This article discussed the natural history of CLC,risk factors for its progression,and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.展开更多
Multiple sclerosis（MS） is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later tr...Multiple sclerosis（MS） is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies（DMTs） for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.展开更多
The inherent complexity of Alzheimer’s disease(AD)and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology.Here we ...The inherent complexity of Alzheimer’s disease(AD)and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology.Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action.Pseudo-irreversible inhibition of the first therapeutic target,human butyrylcholinesterase(hBChE),enhances cholinergic transmission,and thereby provides symptomatic treatment,same as the standard therapeutics in use for AD.Simultaneously,this step also functions as a metabolic activation that liberates a nanomolar selectiveα_(2)-adrenergic antagonist atipamezole,which blocks pathological amyloidß(Aß)-induced and noradrenaline-dependent activation of GSK3ßthat ultimately leads to hyperphosphorylation of tau,thus achieving a disease-modifying effect.Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition,metabolic activation in human plasma,blood-brain barrier permeability,and p.o.bioavailability in mice.Multi-day in vivo treatment with 8 in an Aß-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine,the current drug of choice for AD therapy.Furthermore,decreased GSK3ßactivation and lowered tau phosphorylation were observed in APP/PS1 mice.This surpasses the symptomatic-only treatment with cholinesterase inhibitors,as it directly blocks an essential pathological cascade in AD.Therefore,these multifunctionalα_(2)-adrenergic antagonists-butyrylcholinesterase inhibitors,exemplified by lead compound 8,present an innovative,small molecule-based,disease-modifying approach to treatment of AD.展开更多
Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modif...Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.展开更多
Rheumatoid arthritis(RA)significantly increases the risk of cardiovascular di-seases(CVD),including myocardial infarction(MI),stroke,and heart failure(HF).This association is linked to chronic inflammation,endothelial...Rheumatoid arthritis(RA)significantly increases the risk of cardiovascular di-seases(CVD),including myocardial infarction(MI),stroke,and heart failure(HF).This association is linked to chronic inflammation,endothelial dysfunction,and accelerated atherosclerosis.Patients with RA have a 1.5-2 times higher risk of CVD compared to the general population,and cardiovascular mortality reaches 40%-50%.However,basic anti-inflammatory drugs such as methotrexate reduce the rate of cardiovascular events by 20%-30%due to suppression of systemic inflammation.Biological medications also demonstrate a cardioprotective effect,reducing the risk of MI by 20%-40%,although some(e.g.,tumor necrosis factor α inhibitors)may increase the risk of HF in predisposed patients.Janus kinase inhibitors are associated with an increased risk of thrombosis and cardiovascular events,particularly in patients with pre-existing risk factors.Therefore,optimal control of inflammation in RA can reduce cardiovascular risk;however,drug selection should consider individual safety profiles.Regular monitoring of car-diovascular risk factors and a multidisciplinary approach are key to managing patients with RA and minimizing complications.展开更多
Uveitis is an inflammatory disease affecting the uvea,which includes the iris,ciliary body and choroid(1).Noninfective uveitis is more prevalent in developed countries and primarily impacts individuals of working age,...Uveitis is an inflammatory disease affecting the uvea,which includes the iris,ciliary body and choroid(1).Noninfective uveitis is more prevalent in developed countries and primarily impacts individuals of working age,with a mean onset of around 40 years.It accounts for 5-10%of severe vision impairment globally(1,2).This form of uveitis is often associated with systemic diseases,such as ankylosing spondylosis,juvenile idiopathic arthritis,sarcoidosis and Behcet’s disease(2,3).展开更多
BACKGROUND Juvenile arthritis damage index(JADI)is a tool that measures the degree of aggressiveness of the juvenile idiopathic arthritis(JIA)course and assesses articular[JADI-articular damage(JADI-A)]and extraarticu...BACKGROUND Juvenile arthritis damage index(JADI)is a tool that measures the degree of aggressiveness of the juvenile idiopathic arthritis(JIA)course and assesses articular[JADI-articular damage(JADI-A)]and extraarticular[JADI-extraarticular damage(JADI-E)]damage.While aggressive JIA often requires early bio-logic disease-modified antirheumatic drugs(bDMARDs),the utility of JADI as a predictor of treatment response remains underexplored.AIM To evaluate the potential of JADI as a predictor of bDMARD treatment response in JIA patients.METHODS This prospective study included 112 highly active non-systemic JIA biologic-naïve patients with a mean age of 12.2±4.6 years and a median disease duration of 2.5(interquartile range:1-5)years.Their clinical and radiological assessment,juvenile arthritis disease activity score 71,JADI-A,and JADI-E,were evaluated twice:Before the biologic initiation(baseline)and 12 months after(end of study).At baseline,50%had any damage,with 43%with articular damage and 23%with extraarticular damage.RESULTS During the study,JADI-A/JADI-E improved(33.9%/9.8%),worsened(8.9%/5.4%),or remained unchanged(57.1%/84.8%).Patients with baseline damage had higher markers of JIA activity:Polyarticular course,earlier onset age,ANA-positivity,and more active joints.Patients without initial structural damage(JADI“-”)were more likely(odds ratio=3.8,95%confidence interval:1.6-9.0,P<0.004)to achieve a low degree of activity or remission(46.2%),while on biological therapy,their scores were comparable to JADI-positive(18.3%).Pre-biological joint damage according to the JADI-A index(P=0.003),wrist(P=0.035),elbow(P=0.027),cervical spine limitation of motion(P=0.051),and erosions confirmed by magnetic resonance imaging(P=0.002),were associated with poor response to biological treatment and follow-up JIA activity.CONCLUSION Baseline structural damage in JIA is associated with diminished bDMARDs efficacy,increased disability,and shorter remission duration.JADI enhances conventional clinical risk stratification by facilitating timely initiation of bDMARDs,adherence to treat-to-target strategy and tailored patient care.展开更多
The systemic therapies available for the management of Psoriasis (PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can wo...The systemic therapies available for the management of Psoriasis (PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs (cDMARDs) or biological ones (bDMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus (HBV) and hepatitis C virus (HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen (anti-HBsAg), HBsAg, and antibody to HCV (anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a (CyA) or bDMARDs (etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBsAg and transaminases dosing can be monitored every 3 mo. Concerning PsO patients with chronic HCV infection their management with immunosuppressive drugs is less problematic as compared to those infected by HBV. In fact, HCV reactivation is an extremely rare event after administration of drugs such as CyA or tumor necrosis factor-α inhibitors. As a rule, these patients can be monitored measuring HCV RNA load, and ALT, aspartate transaminase, gamma-glutamyl-transferase, bilirubin, alkaline phosphatase, albumin and platelet every 3-6 mo. The present article provides an updated overview based on more recently reported data on monitoring and managing PsO patients who need systemic antipsoriatic treatment and have HBV or HCV infection as comorbidity.展开更多
Osteoarthritis(OA) is the most common type of arthritis found in the United States' population and is also the most common disease of joints in adults throughout the world with the knee being the most frequently a...Osteoarthritis(OA) is the most common type of arthritis found in the United States' population and is also the most common disease of joints in adults throughout the world with the knee being the most frequently affected of all joints. As the United States' population ages along with the increasing trends in obesity prevalence in other parts of the world, it is expected that the burden of OA on the population, healthcare system, and overall economy will continue to increase in the future without making major improvements in managing knee OA. Numerous therapies aim to reduce symptoms of knee OA and continued research has helped to further understand the complex pathophysiology of its disease mechanism attempting to uncover new potential targets for the treatment of OA. This review article seeks to evaluate the current practices for managing knee OA and discusses emerging therapies on the horizon. These practices include non-pharmacological treatments such as providing patient education and self-management strategies, advising weight loss, strengthening programs, and addressing biomechanical issues with bracing or foot orthoses. Oral analgesics and anti-inflammatories are pharmacologicals that are commonly used and the literature overall supports that some of these medications can be helpful for managing knee OA in the short-term but are less effective for long-term management. Additionally, more prolonged use significantly increases the risk of serious associated side effects that are not too uncommon. Diseasemodifying osteoarthritis drugs are being researched as a treatment modality to potentially halt or slow disease progression but data at this time is limited and continued studies are being conducted to further investigate their effectiveness. Intra-articular injectables are also implemented to manage knee OA ranging from corticosteroids to hyaluronans to more recently plateletrich plasma and even stem cells while several other injection therapies are presently being studied. The goal of developing new treatment strategies for knee OA is to prolong the need for total knee arthroplasty which should be utilized only if other strategies have failed. High tibial osteotomy and unicompartmental knee arthroplasty are potential alternatives if only a single compartment is involved with more data supporting unicompartmental knee arthroplasty as a good treatment option in this scenario. Arthroscopy has been commonly used for many years to treat knee OA to address degenerative articular cartilage and menisci, however, several high-quality studies have shown that it is not a very effective treatment for the majority of cases and should generally not be considered when managing knee OA. Improving the management of knee OA requires a multi-faceted treatment approach along with continuing to broaden our understanding of this complex disease so that therapeutic advancements can continue to be developed with the goal of preventing further disease progression and even potentially reversing the degenerative process.展开更多
Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current...Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current treatment is focused on mitigating the symptoms through the administration of levodopa,rather than on preventing dopaminergic neuronal damage.Therefore,the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson's disease.For instance,N-acetylcysteine,a natural compound with strong antioxidant effects,has been shown to modulate oxidative stress,preventing dopamine-induced cell death.Despite the evidence of neuroprotective and modulatory effects of this drug,as far as we know,it does not induce per se any regenerative process.Therefore,it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation,as stem cell-based strategies.Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson's disease,given its ability to modulate cell viability/preservation of dopaminergic neurons.Such approach represents a shift in the paradigm,showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson's disease.Thus,in this review,we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases,like Parkinson's disease.展开更多
Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acut...Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by proliferative synovitis,which can cause cartilage and bone damage as well as functional limitations.Disease-modifying anti-rheumatic drugs have signifi...Rheumatoid arthritis(RA)is an autoimmune disease characterized by proliferative synovitis,which can cause cartilage and bone damage as well as functional limitations.Disease-modifying anti-rheumatic drugs have significantly improved the prognosis of RA patients.However,people with RA,when combined with hepatitis B virus(HBV)infection,may experience reactivation of HBV during treatment with anti-rheumatic drugs.The outcome of HBV reactivation(HBVr)varies from liver inflammation to liver failure,while insufficient HBV screening in RA patients has been reported in various countries.Therefore,it is necessary to identify patients at high risk before starting immunosuppressive therapy.The immune response plays an important role in anti-HBV infection.However,most anti-rheumatic drugs exert an inhibitory effect on the body’s immune system,resulting in HBVr.Therefore,it is necessary to conduct a comprehensive evaluation based on host factors,viral factors,and drug factors.In this paper,we summarize the mechanism of HBVr,the risk of HBVr caused by anti-rheumatic drugs,and the appropriate diagnosis and treatment process for RA patients so that clinicians can have a more comprehensive understanding of HBVr in RA patients.展开更多
With a 5.3%of the global population involved,hepatitis B virus(HBV)is a major public health challenge requiring an urgent response.After a possible acute phase,the natural history of HBV infection can progress in chro...With a 5.3%of the global population involved,hepatitis B virus(HBV)is a major public health challenge requiring an urgent response.After a possible acute phase,the natural history of HBV infection can progress in chronicity.Patients with overt or occult HBV infection can undergo HBV reactivation(HBVr)in course of immunosuppressive treatments that,apart from oncological and hematological diseases,are also used in rheumatologic,gastrointestinal,neurological and dermatological settings,as well as to treat severe acute respiratory syndrome coronavirus 2 infection.The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition.The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence.The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed.The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status.Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.展开更多
Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly con...Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.展开更多
In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible ...In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.展开更多
Tofacitinib is an immunosuppressive and disease-modifying therapy in rheumatoid arthritis.It may result in many infections flaring up.It is important to take precautions of all kinds(cardiovascular,malignancy,infectio...Tofacitinib is an immunosuppressive and disease-modifying therapy in rheumatoid arthritis.It may result in many infections flaring up.It is important to take precautions of all kinds(cardiovascular,malignancy,infections etc.)before starting tofacitinib.In this article,we have highlighted important steps where we need to take precautions before starting tofacitinib.展开更多
A recent study published in World J Clin Cases addressed the optimal non-steroidal anti-inflammatory drugs(NSAIDs)for juvenile idiopathic arthritis(JIA).Herein,we outline the progress in drug therapy of JIA.NSAIDs hav...A recent study published in World J Clin Cases addressed the optimal non-steroidal anti-inflammatory drugs(NSAIDs)for juvenile idiopathic arthritis(JIA).Herein,we outline the progress in drug therapy of JIA.NSAIDs have traditionally been the primary treatment for all forms of JIA.NSAIDs are symptom-relief medications,and well tolerated by patients.Additionally,the availability of selective NSAIDs further lower the gastrointestinal adverse reactions compared with traditional NSAIDs.Glucocorticoid is another kind of symptom-relief medications with potent anti-inflammatory effect.However,the frequent adverse events limit the clinical use.Both NSAIDs and glucocorticoid fail to ease or pre-vent joint damage,and the breakthrough comes along with the disease-mo-difying antirheumatic drugs(DMARDs).DMARDs can prevent disease pro-gression and reduce joint destruction.Particularly,the emergence of biologic DMARDs(bDMARDs)has truly revolutionized the therapeutics of JIA,compared with conventional synthetic DMARDs.As a newly developed class of drugs,the places of most bDMARDs in the management of JIA remain to be well estab-lished.Nevertheless,the continuous evolution of bDMARDs raises hopes of improving long-term disease outcomes for JIA.展开更多
Biologic agents have ushered a new era in the treatment of inflammatory rheumatic diseases.In recent years,several biologic agents have been approved by food and drug administration and have significantly improved out...Biologic agents have ushered a new era in the treatment of inflammatory rheumatic diseases.In recent years,several biologic agents have been approved by food and drug administration and have significantly improved outcomes for patients with immune mediatedinflammatory disorders including rheumatic and inflammatory bowel diseases.The most common used biologic therapeutic agents are tumor necrosis factor inhibitors(etanercept,infliximab,adalimumab,certolizumab pegol,and golimumab),an interleukin(IL)-6 inhibitor(tocilizumab),an IL-1 receptor antagonist(anakinra),an anti-CD-20 antibody(rituximab),and a T cell costimulation modulator(abatacept).Their use during pregnancy has been controversial because of absence of controlled studies which have enrolled pregnant women.This brief overview provides published data on use of biologic agents for the treatment of rheumatic diseases in pregnancy.展开更多
India is no exception to the economic setback due to coronavirus disease 2019 (COVID-19). Loss of jobs and income dramatically impacts the health care cost of chronic disease management. Rheumatoid arthritis is a chro...India is no exception to the economic setback due to coronavirus disease 2019 (COVID-19). Loss of jobs and income dramatically impacts the health care cost of chronic disease management. Rheumatoid arthritis is a chronic condition with a high-cost implication. With the outbreak of COVID-19, there is uncertainty about continuing immunosuppressive therapy for rheumatoid arthritis for several reasons. In this milieu, we undertook a prospective observational study to observe the use of Janus Kinase (JAK) inhibitors in a hospital-based rheumatology service in Eastern India during the pandemic period (21 March 2020 to 31 July 2020). Forty-two patients with rheumatoid arthritis were receiving treatment with JAK inhibitors. Twenty-four patients visited the Outpatient Department (OPD) during the COVID-19 pandemic. All of them were COVID-negative, but few of the patients had influenza-like symptoms. Patients faced up to a 25% reduction in their annual income during the COVID-19 pandemic. Of 24 patients, four patients had stopped treatment with JAK inhibitors owing to financial constraints or initial non-availability of medications during the lockdown. In this study, adherence to JAK inhibitors was substantially high even in the face of income curtailment during the COVID-19 pandemic.展开更多
文摘BACKGROUND Immune checkpoint inhibitor(ICI)-induced rheumatic immune-related adverse events(ir AEs)have been infrequently reported,and the treatment of severe or refractory arthritis as ir AEs has not been established yet.CASE SUMMARY The patient was a 67-year-old man with a history of well-controlled foot psoriasis who presented with polyarthralgia.He had received pembrolizumab for metastatic gastric adenocarcinoma 2 mo previously.Physical examination revealed erythematous swelling in the distal interphalangeal joints,left shoulder,and both knees.He had plaque psoriasis with psoriatic nail dystrophy and dactylitis in the distal joints of the fingers and toes.Inflammatory markers including C-reactive protein and erythrocyte sedimentation rate were elevated but rheumatoid factor and anticyclic citrullinated peptide antibody were negative.The patient was diagnosed with psoriatic arthritis(PsA)and started on methylprednisolone 1 mg/kg/day after pembrolizumab discontinuation.However,despite 1 wk of methylprednisolone treatment,PsA worsened;hence,leflunomide and methotrexate were started.After 4 wk of steroid treatment,PsA worsened and improved repeatedly with steroid tapering.Therefore,the therapy was intensified to include etanercept,a tumor necrosis factor inhibitor,which ultimately resulted in adequate PsA control.CONCLUSION This is the first report of ICI-induced PsA in a gastric cancer patient.Some rheumatic ir AEs with refractory severe arthritis may require disease-modifying anti-rheumatic drugs and long-term management.
文摘Compensated liver cirrhosis(CLC)is defined as cirrhosis with one or more decompensating events,such as ascites,variceal haemorrhage,or hepatic encephalopathy.Patients with CLC are largely asymptomatic with preserved hepatic function.The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors.The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis,as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years.Furthermore,early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition.With the advent of effective non-invasive tools for detecting hepatic fibrosis,more and more patients with CLC are currently being recognised.This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or,at the very least,prevent its progression.There are numerous emerging approaches for preventing or delaying decompensation in CLC patients.A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression,and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension.Additionally,address-ing various cofactors(such as obesity,diabetes,dyslipidaemia,and alcoholism)and precipitating factors(such as infection,viral hepatitis,and hepatotoxic drugs)that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC.However,high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these diseasemodifying techniques for CLC patients.This article discussed the natural history of CLC,risk factors for its progression,and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.
文摘Multiple sclerosis（MS） is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies（DMTs） for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.
基金supported by the Slovenian Research Agency(ARRS),Research Core Funding Nos.P1-0208,P1-0012,P40127,and P4-0053a young researcher grant to A.Mthe grant from China-Central and Eastern European Countries University joint education program(No.2022248).
文摘The inherent complexity of Alzheimer’s disease(AD)and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology.Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action.Pseudo-irreversible inhibition of the first therapeutic target,human butyrylcholinesterase(hBChE),enhances cholinergic transmission,and thereby provides symptomatic treatment,same as the standard therapeutics in use for AD.Simultaneously,this step also functions as a metabolic activation that liberates a nanomolar selectiveα_(2)-adrenergic antagonist atipamezole,which blocks pathological amyloidß(Aß)-induced and noradrenaline-dependent activation of GSK3ßthat ultimately leads to hyperphosphorylation of tau,thus achieving a disease-modifying effect.Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition,metabolic activation in human plasma,blood-brain barrier permeability,and p.o.bioavailability in mice.Multi-day in vivo treatment with 8 in an Aß-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine,the current drug of choice for AD therapy.Furthermore,decreased GSK3ßactivation and lowered tau phosphorylation were observed in APP/PS1 mice.This surpasses the symptomatic-only treatment with cholinesterase inhibitors,as it directly blocks an essential pathological cascade in AD.Therefore,these multifunctionalα_(2)-adrenergic antagonists-butyrylcholinesterase inhibitors,exemplified by lead compound 8,present an innovative,small molecule-based,disease-modifying approach to treatment of AD.
文摘Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.
文摘Rheumatoid arthritis(RA)significantly increases the risk of cardiovascular di-seases(CVD),including myocardial infarction(MI),stroke,and heart failure(HF).This association is linked to chronic inflammation,endothelial dysfunction,and accelerated atherosclerosis.Patients with RA have a 1.5-2 times higher risk of CVD compared to the general population,and cardiovascular mortality reaches 40%-50%.However,basic anti-inflammatory drugs such as methotrexate reduce the rate of cardiovascular events by 20%-30%due to suppression of systemic inflammation.Biological medications also demonstrate a cardioprotective effect,reducing the risk of MI by 20%-40%,although some(e.g.,tumor necrosis factor α inhibitors)may increase the risk of HF in predisposed patients.Janus kinase inhibitors are associated with an increased risk of thrombosis and cardiovascular events,particularly in patients with pre-existing risk factors.Therefore,optimal control of inflammation in RA can reduce cardiovascular risk;however,drug selection should consider individual safety profiles.Regular monitoring of car-diovascular risk factors and a multidisciplinary approach are key to managing patients with RA and minimizing complications.
文摘Uveitis is an inflammatory disease affecting the uvea,which includes the iris,ciliary body and choroid(1).Noninfective uveitis is more prevalent in developed countries and primarily impacts individuals of working age,with a mean onset of around 40 years.It accounts for 5-10%of severe vision impairment globally(1,2).This form of uveitis is often associated with systemic diseases,such as ankylosing spondylosis,juvenile idiopathic arthritis,sarcoidosis and Behcet’s disease(2,3).
文摘BACKGROUND Juvenile arthritis damage index(JADI)is a tool that measures the degree of aggressiveness of the juvenile idiopathic arthritis(JIA)course and assesses articular[JADI-articular damage(JADI-A)]and extraarticular[JADI-extraarticular damage(JADI-E)]damage.While aggressive JIA often requires early bio-logic disease-modified antirheumatic drugs(bDMARDs),the utility of JADI as a predictor of treatment response remains underexplored.AIM To evaluate the potential of JADI as a predictor of bDMARD treatment response in JIA patients.METHODS This prospective study included 112 highly active non-systemic JIA biologic-naïve patients with a mean age of 12.2±4.6 years and a median disease duration of 2.5(interquartile range:1-5)years.Their clinical and radiological assessment,juvenile arthritis disease activity score 71,JADI-A,and JADI-E,were evaluated twice:Before the biologic initiation(baseline)and 12 months after(end of study).At baseline,50%had any damage,with 43%with articular damage and 23%with extraarticular damage.RESULTS During the study,JADI-A/JADI-E improved(33.9%/9.8%),worsened(8.9%/5.4%),or remained unchanged(57.1%/84.8%).Patients with baseline damage had higher markers of JIA activity:Polyarticular course,earlier onset age,ANA-positivity,and more active joints.Patients without initial structural damage(JADI“-”)were more likely(odds ratio=3.8,95%confidence interval:1.6-9.0,P<0.004)to achieve a low degree of activity or remission(46.2%),while on biological therapy,their scores were comparable to JADI-positive(18.3%).Pre-biological joint damage according to the JADI-A index(P=0.003),wrist(P=0.035),elbow(P=0.027),cervical spine limitation of motion(P=0.051),and erosions confirmed by magnetic resonance imaging(P=0.002),were associated with poor response to biological treatment and follow-up JIA activity.CONCLUSION Baseline structural damage in JIA is associated with diminished bDMARDs efficacy,increased disability,and shorter remission duration.JADI enhances conventional clinical risk stratification by facilitating timely initiation of bDMARDs,adherence to treat-to-target strategy and tailored patient care.
文摘The systemic therapies available for the management of Psoriasis (PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs (cDMARDs) or biological ones (bDMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus (HBV) and hepatitis C virus (HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen (anti-HBsAg), HBsAg, and antibody to HCV (anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a (CyA) or bDMARDs (etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBsAg and transaminases dosing can be monitored every 3 mo. Concerning PsO patients with chronic HCV infection their management with immunosuppressive drugs is less problematic as compared to those infected by HBV. In fact, HCV reactivation is an extremely rare event after administration of drugs such as CyA or tumor necrosis factor-α inhibitors. As a rule, these patients can be monitored measuring HCV RNA load, and ALT, aspartate transaminase, gamma-glutamyl-transferase, bilirubin, alkaline phosphatase, albumin and platelet every 3-6 mo. The present article provides an updated overview based on more recently reported data on monitoring and managing PsO patients who need systemic antipsoriatic treatment and have HBV or HCV infection as comorbidity.
文摘Osteoarthritis(OA) is the most common type of arthritis found in the United States' population and is also the most common disease of joints in adults throughout the world with the knee being the most frequently affected of all joints. As the United States' population ages along with the increasing trends in obesity prevalence in other parts of the world, it is expected that the burden of OA on the population, healthcare system, and overall economy will continue to increase in the future without making major improvements in managing knee OA. Numerous therapies aim to reduce symptoms of knee OA and continued research has helped to further understand the complex pathophysiology of its disease mechanism attempting to uncover new potential targets for the treatment of OA. This review article seeks to evaluate the current practices for managing knee OA and discusses emerging therapies on the horizon. These practices include non-pharmacological treatments such as providing patient education and self-management strategies, advising weight loss, strengthening programs, and addressing biomechanical issues with bracing or foot orthoses. Oral analgesics and anti-inflammatories are pharmacologicals that are commonly used and the literature overall supports that some of these medications can be helpful for managing knee OA in the short-term but are less effective for long-term management. Additionally, more prolonged use significantly increases the risk of serious associated side effects that are not too uncommon. Diseasemodifying osteoarthritis drugs are being researched as a treatment modality to potentially halt or slow disease progression but data at this time is limited and continued studies are being conducted to further investigate their effectiveness. Intra-articular injectables are also implemented to manage knee OA ranging from corticosteroids to hyaluronans to more recently plateletrich plasma and even stem cells while several other injection therapies are presently being studied. The goal of developing new treatment strategies for knee OA is to prolong the need for total knee arthroplasty which should be utilized only if other strategies have failed. High tibial osteotomy and unicompartmental knee arthroplasty are potential alternatives if only a single compartment is involved with more data supporting unicompartmental knee arthroplasty as a good treatment option in this scenario. Arthroscopy has been commonly used for many years to treat knee OA to address degenerative articular cartilage and menisci, however, several high-quality studies have shown that it is not a very effective treatment for the majority of cases and should generally not be considered when managing knee OA. Improving the management of knee OA requires a multi-faceted treatment approach along with continuing to broaden our understanding of this complex disease so that therapeutic advancements can continue to be developed with the goal of preventing further disease progression and even potentially reversing the degenerative process.
基金the financial support from Prémios Santa Casa Neurociências Prize Mantero Belard for Neurodegenerative Diseases Research(MB-28-2019)supported by the European Regional Development Fund(FEDER)+8 种基金through the Competitiveness Internationalization Operational Programme(POCI)by National fundsthrough the Foundation for Science and Technology(FCT)under the scope of projects UIDB/50026/2020UIDP/50026/2020 and POCI-01-0145-FEDER-029751developed under the scope of the project NORTE-01-0145-FEDER-000023supported by the Northern Portugal Regional Operational Programme(NORTE 2020)under the Portugal 2020 Partnership Agreement,through the European Regional Development Fund(FEDER)funded by ICVS Scientific Microscopy Platform,member of the national infrastructure PPBI-Portuguese Platform of Bioimaging(PPBI-POCI-01-0145-FEDER-022122)(to FGT)。
文摘Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current treatment is focused on mitigating the symptoms through the administration of levodopa,rather than on preventing dopaminergic neuronal damage.Therefore,the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson's disease.For instance,N-acetylcysteine,a natural compound with strong antioxidant effects,has been shown to modulate oxidative stress,preventing dopamine-induced cell death.Despite the evidence of neuroprotective and modulatory effects of this drug,as far as we know,it does not induce per se any regenerative process.Therefore,it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation,as stem cell-based strategies.Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson's disease,given its ability to modulate cell viability/preservation of dopaminergic neurons.Such approach represents a shift in the paradigm,showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson's disease.Thus,in this review,we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases,like Parkinson's disease.
文摘Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by proliferative synovitis,which can cause cartilage and bone damage as well as functional limitations.Disease-modifying anti-rheumatic drugs have significantly improved the prognosis of RA patients.However,people with RA,when combined with hepatitis B virus(HBV)infection,may experience reactivation of HBV during treatment with anti-rheumatic drugs.The outcome of HBV reactivation(HBVr)varies from liver inflammation to liver failure,while insufficient HBV screening in RA patients has been reported in various countries.Therefore,it is necessary to identify patients at high risk before starting immunosuppressive therapy.The immune response plays an important role in anti-HBV infection.However,most anti-rheumatic drugs exert an inhibitory effect on the body’s immune system,resulting in HBVr.Therefore,it is necessary to conduct a comprehensive evaluation based on host factors,viral factors,and drug factors.In this paper,we summarize the mechanism of HBVr,the risk of HBVr caused by anti-rheumatic drugs,and the appropriate diagnosis and treatment process for RA patients so that clinicians can have a more comprehensive understanding of HBVr in RA patients.
文摘With a 5.3%of the global population involved,hepatitis B virus(HBV)is a major public health challenge requiring an urgent response.After a possible acute phase,the natural history of HBV infection can progress in chronicity.Patients with overt or occult HBV infection can undergo HBV reactivation(HBVr)in course of immunosuppressive treatments that,apart from oncological and hematological diseases,are also used in rheumatologic,gastrointestinal,neurological and dermatological settings,as well as to treat severe acute respiratory syndrome coronavirus 2 infection.The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition.The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence.The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed.The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status.Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.
文摘Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.
文摘In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.
文摘Tofacitinib is an immunosuppressive and disease-modifying therapy in rheumatoid arthritis.It may result in many infections flaring up.It is important to take precautions of all kinds(cardiovascular,malignancy,infections etc.)before starting tofacitinib.In this article,we have highlighted important steps where we need to take precautions before starting tofacitinib.
文摘A recent study published in World J Clin Cases addressed the optimal non-steroidal anti-inflammatory drugs(NSAIDs)for juvenile idiopathic arthritis(JIA).Herein,we outline the progress in drug therapy of JIA.NSAIDs have traditionally been the primary treatment for all forms of JIA.NSAIDs are symptom-relief medications,and well tolerated by patients.Additionally,the availability of selective NSAIDs further lower the gastrointestinal adverse reactions compared with traditional NSAIDs.Glucocorticoid is another kind of symptom-relief medications with potent anti-inflammatory effect.However,the frequent adverse events limit the clinical use.Both NSAIDs and glucocorticoid fail to ease or pre-vent joint damage,and the breakthrough comes along with the disease-mo-difying antirheumatic drugs(DMARDs).DMARDs can prevent disease pro-gression and reduce joint destruction.Particularly,the emergence of biologic DMARDs(bDMARDs)has truly revolutionized the therapeutics of JIA,compared with conventional synthetic DMARDs.As a newly developed class of drugs,the places of most bDMARDs in the management of JIA remain to be well estab-lished.Nevertheless,the continuous evolution of bDMARDs raises hopes of improving long-term disease outcomes for JIA.
文摘Biologic agents have ushered a new era in the treatment of inflammatory rheumatic diseases.In recent years,several biologic agents have been approved by food and drug administration and have significantly improved outcomes for patients with immune mediatedinflammatory disorders including rheumatic and inflammatory bowel diseases.The most common used biologic therapeutic agents are tumor necrosis factor inhibitors(etanercept,infliximab,adalimumab,certolizumab pegol,and golimumab),an interleukin(IL)-6 inhibitor(tocilizumab),an IL-1 receptor antagonist(anakinra),an anti-CD-20 antibody(rituximab),and a T cell costimulation modulator(abatacept).Their use during pregnancy has been controversial because of absence of controlled studies which have enrolled pregnant women.This brief overview provides published data on use of biologic agents for the treatment of rheumatic diseases in pregnancy.
文摘India is no exception to the economic setback due to coronavirus disease 2019 (COVID-19). Loss of jobs and income dramatically impacts the health care cost of chronic disease management. Rheumatoid arthritis is a chronic condition with a high-cost implication. With the outbreak of COVID-19, there is uncertainty about continuing immunosuppressive therapy for rheumatoid arthritis for several reasons. In this milieu, we undertook a prospective observational study to observe the use of Janus Kinase (JAK) inhibitors in a hospital-based rheumatology service in Eastern India during the pandemic period (21 March 2020 to 31 July 2020). Forty-two patients with rheumatoid arthritis were receiving treatment with JAK inhibitors. Twenty-four patients visited the Outpatient Department (OPD) during the COVID-19 pandemic. All of them were COVID-negative, but few of the patients had influenza-like symptoms. Patients faced up to a 25% reduction in their annual income during the COVID-19 pandemic. Of 24 patients, four patients had stopped treatment with JAK inhibitors owing to financial constraints or initial non-availability of medications during the lockdown. In this study, adherence to JAK inhibitors was substantially high even in the face of income curtailment during the COVID-19 pandemic.
